Methylation and Mutation Assay to Personalize PARP Inhibitor Therapy

项目摘要/摘要 目前提案的总体目标是开发一种临床上有用的PARP抑制物(PARPI)预测因子 对不太可能受益的患者的额外毒性和成本的敏感性/抵抗力。我们的假设是一个 在治疗开始前立即进行的联合突变和甲基化分析将提供 PARPI反应的有用预测因子。为了验证这一假设，我们的方法是将高吞吐量和 关键同源重组基因突变分析的甲基化定量分析。我们会改进的 我们的检测使用了银行肿瘤组织和福尔马林固定石蜡包埋(FFPE)的肿瘤标本。 2期PARPI试验，然后使用4个大型3I期随机对照试验的样本来测试这些分析 (RCT)在使用三种不同PARPI的OC中。 我们提出三个具体目标： 目的1：建立临床分级定量甲基化检测方法和甲基化与突变联合检测方法 (MMA)以确定对PARP抑制剂反应最好的BRCA野生型癌症。 目的2：在一项复发卵巢的随机对照试验中，验证MMA作为PARPI反应的预测因子 癌症。 目的3：在3个初步治疗的随机对照试验中，验证MMA作为PARPI反应的预测因子 高级OC。

PROJECT SUMMARY/ABSTRACT The overall goal of the current proposal is to develop a clinically useful predictor of PARP inhibitor (PARPi) sensitivity/resistance to spare toxicities and cost for patients unlikely to derive benefit. Our hypothesis is that a combined mutation and methylation analysis performed immediately before initiation of therapy will provide a useful predictor of PARPi response. To test this hypothesis, our approach is to combine a high throughput and quantitative methylation assay with mutational analysis of key homologous recombination genes. We will refine our assay using banked tumor tissues and formalin fixed paraffin embedded (FFPE) neoplastic samples from a phase 2 PARPi trial, then test these assays using samples from 4 large phase 3I randomized controlled trials (RCT) in OC that employ three different PARPi. We propose three specific aims: Aim 1: Develop a clinical grade, quantitative methylation assay and a combined methylation and mutation assay (MMA) to define those BRCA wildtype cancers with best response to PARP inhibitors. Aim 2: Validate MMA as a predictor of PARPi response in a randomized controlled trial of recurrent ovarian carcinoma. Aim 3: Validate MMA as a predictor of PARPi response in 3 randomized controlled trials for primary treatment of advanced OC.